{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:44:57Z","timestamp":1787064297828,"version":"build-2736575974"},"reference-count":56,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T00:00:00Z","timestamp":1720656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Florence","award":["RICATEN21"],"award-info":[{"award-number":["RICATEN21"]}]},{"name":"University of Florence","award":["RICATEN22"],"award-info":[{"award-number":["RICATEN22"]}]},{"name":"University of Florence","award":["RICATEN23"],"award-info":[{"award-number":["RICATEN23"]}]},{"name":"University of Florence","award":["EX-POST 2021"],"award-info":[{"award-number":["EX-POST 2021"]}]},{"name":"Compagnia di San Paolo","award":["RICATEN21"],"award-info":[{"award-number":["RICATEN21"]}]},{"name":"Compagnia di San Paolo","award":["RICATEN22"],"award-info":[{"award-number":["RICATEN22"]}]},{"name":"Compagnia di San Paolo","award":["RICATEN23"],"award-info":[{"award-number":["RICATEN23"]}]},{"name":"Compagnia di San Paolo","award":["EX-POST 2021"],"award-info":[{"award-number":["EX-POST 2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and hCA XII. Indeed, these hybrid compounds contain both P-gp and hCA XII binding groups on the two nitrogen atoms of the heterocyclic ring. All compounds showed good inhibitory activity on each protein (P-gp and hCA XII) studied individually, and many of them showed a synergistic effect in the resistant HT29\/DOX and A549\/DOX cell lines which overexpress both the target proteins. In particular, compound 33 displayed the best activity by enhancing the cytotoxicity and intracellular accumulation of doxorubicin in HT29\/DOX and A549\/DOX cells, thus resulting as promising P-gp-mediated MDR reverser with a synergistic mechanism. Furthermore, compounds 13, 27 and 32 induced collateral sensitivity (CS) in MDR cells, as they were more cytotoxic in resistant cells than in the sensitive ones; their CS mechanisms were extensively investigated.<\/jats:p>","DOI":"10.3390\/molecules29143290","type":"journal-article","created":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T08:16:57Z","timestamp":1720772217000},"page":"3290","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Dual Inhibitors of P-gp and Carbonic Anhydrase XII (hCA XII) against Tumor Multidrug Resistance with Piperazine Scaffold"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0861-0706","authenticated-orcid":false,"given":"Laura","family":"Braconi","sequence":"first","affiliation":[{"name":"Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9787-4836","authenticated-orcid":false,"given":"Chiara","family":"Riganti","sequence":"additional","affiliation":[{"name":"Oncological Pharmacology Laboratory and Molecular Biotechnology Center \u201cGuido Tarone\u201d, Department of Oncology, University of Turin, Piazza Nizza 44, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7980-6853","authenticated-orcid":false,"given":"Astrid","family":"Parenti","sequence":"additional","affiliation":[{"name":"Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8777-6674","authenticated-orcid":false,"given":"Marta","family":"Cecchi","sequence":"additional","affiliation":[{"name":"Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3342-702X","authenticated-orcid":false,"given":"Alessio","family":"Nocentini","sequence":"additional","affiliation":[{"name":"Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5631-8769","authenticated-orcid":false,"given":"Gianluca","family":"Bartolucci","sequence":"additional","affiliation":[{"name":"Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Menicatti","sequence":"additional","affiliation":[{"name":"Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0713-3151","authenticated-orcid":false,"given":"Marialessandra","family":"Contino","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Drug Sciences, University of Bari \u201cA. 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Moro\u201d, via Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5881-6550","authenticated-orcid":false,"given":"Dina","family":"Manetti","sequence":"additional","affiliation":[{"name":"Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5685-3403","authenticated-orcid":false,"given":"Maria Novella","family":"Romanelli","sequence":"additional","affiliation":[{"name":"Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9705-3875","authenticated-orcid":false,"given":"Elisabetta","family":"Teodori","sequence":"additional","affiliation":[{"name":"Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1146\/annurev.med.53.082901.103929","article-title":"Mechanisms of Cancer Drug Resistance","volume":"53","author":"Gottesman","year":"2002","journal-title":"Annu. 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